Abstract
BackgroundNumerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive. Here, we present a model of regression and latency of metastases following primary tumor excision and identify potential underlying mechanisms.ResultsUsing MDA-MB-231HM human breast cancer cells that express highly sensitive luciferase, we monitored early development stages of spontaneous metastases in BALB/c nu/nu mice. Removal of the primary tumor caused marked regression of micro-metastases, but not of larger metastases, and in vivo supplementation of tumor secretome diminished this regression, suggesting that primary tumor-secreted factors promote early metastatic growth. Correspondingly, MDA-MB-231HM-conditioned medium increased in vitro tumor proliferation and adhesion and reduced apoptosis. To identify specific mediating factors, cytokine array and proteomic analysis of MDA-MB-231HM secretome were conducted. The results identified significant enrichment of angiogenesis, growth factor binding and activity, focal adhesion, and metalloprotease and apoptosis regulation processes. Neutralization of MDA-MB-231HM-secreted key mediators of these processes, IL-8, PDGF-AA, Serpin E1 (PAI-1), and MIF, each antagonized secretome-induced proliferation. Moreover, their in vivo simultaneous blockade in the presence of the primary tumor arrested the development of micro-metastases. Interestingly, in the METABRIC cohort of breast cancer patients, elevated expression of Serpin E1, IL-8, or the four factors combined predicted poor survival.ConclusionsThese results demonstrate regression and latency of micro-metastases following primary tumor excision and a crucial role for primary tumor secretome in promoting early metastatic growth in MDA-MB-231HM xenografts. If generalized, such findings can suggest novel approaches to control micro-metastases and minimal residual disease.
Highlights
Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive
A dramatic decrease in metastatic signal, of up to 100-fold, was evident in mice along the 24 h following tumor excision, p < 0.0001 (Fig. 1a, b). This decrease occurred gradually along the first 24 h, and seemed to continue for another 1–2 days thereafter, as evident in Additional file 1: Fig. S1. These metastases have regressed into latent foci, as (i) no increase in in vivo bioluminescent signal occurred for 50 days postexcision (Fig. 1b, c) and as (ii) microscopic malignant foci were evident on both the day after tumor excision and 50 days later, as confirmed by hematoxylin and eosin (H&E) staining of the lungs and lymph nodes (Fig. 1d)
In the breast cancer cohort, studying each factor alone, high levels of either Serpin E1 and IL-8 were associated with poor survival (p < 0.0001 and p = 0.0016, respectively), whereas high expression levels of migration inhibitory factor (MIF) and platelet-derived growth factor-aa (PDGF-AA) did not predict poor survival (Fig. 4a–d). In both the breast cancer cohort and the lung adenocarcinoma cohort, we found that high protein levels of all four factors (IL-8, PDGF-AA, Serpin E1, and MIF) were associated with significantly lower survival (p < 0.0001 and p < 0.05, respectively) (Fig. 4e, Additional file 1: Fig. S3)
Summary
Numerous case studies have reported spontaneous regression of recognized metastases following primary tumor excision, but underlying mechanisms are elusive. Neutralization of MDA-MB-231HM-secreted key mediators of these processes, IL-8, PDGF-AA, Serpin E1 (PAI-1), and MIF, each antagonized secretome-induced proliferation Their in vivo simultaneous blockade in the presence of the primary tumor arrested the development of micro-metastases. Various case studies report the opposite effect: spontaneous post-operative regression of evident cancer metastases or malignant foci [4,5,6,7,8]. Several underlying mechanisms have been suggested to elicit spontaneous post-operative regression of residual malignant foci [12, 15, 16], including surgical trauma [5], and elimination of stimulating factors secreted by the primary tumor or induced by its presence [16]. The need to study potential interactions between the primary tumor (PT) and metastases is stressed by the current realization that the presence of a primary tumor is a systemic disease and that a continuous crosstalk between the PT, its microenvironment, and distant organs plays a significant role in disease etiology and progression [17, 18]
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